Enzyme Reverses Memory Loss in Alzheimer’s Mouse Model

Increasing the amount of a specific enzyme in the brain partially restores memory in a mouse model for Alzheimer’s disease (AD), researchers say. The results could eventually lead to new treatments for AD or other neurodegenerative disorders.

Previous studies have shown that an abnormal accumulation of beta amyloid in the brain interferes with the formation of memories and is central to the development of AD. Because of this, many researchers are working to develop therapies that will block the production of beta amyloid or remove it from the body. However, beta amyloid is needed for cholesterol processing and other important functions, so removing it entirely could be detrimental.

The new study suggests that increasing the amount of an enzyme called ubiquitin c-terminal hydrolase L1 (Uch-L1) can improve brain function without reducing the amount of beta amyloid in the brain. Uch-L1 is important for the proper function of proteasomes -- tiny compartments inside cells that act as a protein disposal system. Researchers have found evidence of proteasome dysfunction in AD, Parkinson’s disease, and other neurodegenerative disorders. They also have found that Uch-L1 is decreased in the presence of beta amyloid and in the brains of people with AD. The new study was designed to test how Uch-L1 affects memory and the changes in synapses that underlie memory (these changes are called long-term potentiation or LTP).

“This is the first study to show that improving the function of proteasomes can improve function in the brain,” says Michael Shelanski, M.D., Ph.D., of Columbia University in New York, who helped lead the research. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the August 25, 2006, issue of the journal Cell.

The researchers found that a compound which inhibits Uch-L1 reduced LTP in brain slices from the hippocampus, a brain region known to be important for memory, in mice. Next, the investigators fused Uch-L1 to a protein that helped it enter cells. Treating brain slices from normal mice with this fused protein before adding beta amyloid blocked the amyloid's detrimental effects on LTP. Adding Uch-L1 to brain slices from a mouse model of AD caused the amount of LTP, which is usually lower than average in these animals, to increase to normal levels.

Next, the investigators injected the Uch-L1 inhibitor into mice and studied its effects on learning and memory. The mice were placed in a new environment — a box — where they heard a sound that was paired with a mild foot shock. The investigators measured how well the mice learned by documenting how much they "froze" with fear in response to being placed in the box or hearing the sound.

Mice treated with the Uch-L1 inhibitor froze 35 percent less often than control mice when placed in the box, the researchers found. This difference lasted at least 21 days. In contrast, increasing Uch-L1 in mice with symptoms of AD greatly increased the mice's freezing responses when placed in the box. Their learned responses improved to about 85 percent of normal. There was no change in the amount of beta amyloid in these mice, and the treatment did not appear to cause any side effects, Dr. Shelanski says.

The Uch-L1 treatment increased the mice's freezing time only in response to the box, not the sound, the researchers note. Contextual learning, such as learning to associate a box with danger, occurs in the hippocampus, whereas learning that is related to sound and other cues is processed in a part of the brain called the amygdala. The results suggest that Uch-L1 may be important for learning in the hippocampus but not the amygdala.

While the exact way that Uch-L1 improves contextual learning is still unknown, the researchers suspect that reducing the activity of Uch-L1 in the proteasome may prevent breakdown of a protein piece called the protein kinase A regulatory subunit, or PKA-R. Previous studies have shown that this protein subunit restricts Uch-L1 activity and LTP. "If the proteasome is inactive, the regulatory subunits may build up," Dr. Shelanski suggests.

While single injections of Uch-L1 did not reduce levels of beta amyloid in the mice, it is possible that a more prolonged treatment would have this effect, the investigators say. Improving the function of proteasomes may help them remove toxic forms of beta amyloid from cells. The Uch-L1 treatment may also block beta-amyloid's harmful effects in other ways.

“Neurodegenerative diseases have in common the toxic accumulation of proteins, which are either expressed at abnormal levels or not cleared properly from the brain. These findings are exciting because they suggest a way to potentially improve the brain’s ability to clear away these harmful proteins. This approach may work for a variety of different diseases,” says Diane Murphy, Ph.D., the NINDS program director for Dr. Shelanski's grant.

Dr. Shelanski and his colleagues are now planning studies that will help to define exactly how beta amyloid interferes with proteasomes and affects Uch-L1, and how decreasing Uch-L1 affects brain function. They also are planning to test the role of Uch-L1 in models for Parkinson's disease, amyotrophic lateral sclerosis, and other disorders. If their experiments are successful, researchers may eventually be able to develop new ways of treating AD and other disorders by increasing the amount of Uch-L1. Such therapies could be used alone or in combination with other treatments that reduce the amount of beta amyloid in the brain.

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.